We have observed that mutations at the H-2Kb locus can alter histocompatibble tumor resistance. The model system of P815 mastocytoma (DBA/2 origin) transplanted into DBA/2 or (C57BL/6 x DBA/2)Fl mice has been extensively characterized. The standard B6D2Fl hybrids consistently live approximately 30% longer than the DBA/2 mice. This hybrid effect is transplantable into lethally irradiated DBA/2 mice with anti thy-1 plus C treated B6D2Fl bone marrow. Using combinations of B6D2Fl and DBA/2 mice, radiation chimera studies demonstrate that this hybrid effect is conferred by Fl bone marrow cells which function optimally if they mature in, or under the influence of, Fl thymus epithelium. Comparing the combinations (B6 mutant x DBA/2)Fl to B6D2Fl after P815 injection, there are several different "mutant hybrids" (B6mD2Fl) which die well before B6D2Fl and at least one B6mD2Fl which may have an increased life span compared to the "wild type" hybrid B6D2Fl. Several of the mutant H-2Kb molecules from these B6 mutant parental strains have been shown to differ by only one or two amino acids. This means that subtle amino acid changes in the H-2K molecule of one haplotype in the histocompatible host can profoundly influence tumor resistance. The purpose of this project is to extend these genetic observations using additional mutants and formal segregation studies and to perform chimera experiments to determine whether the genetic requirements for bone marrow and thymus epithelium can function through the H-2Kb molecule. These studies are important because they could reveal how a single amino acid substitution on a single product of the major histocompatibility complex can influence resistance to a histocompatible tumor. Understanding the precise mechanisms that account for survival differences among these Fl hybrids after injection with the same histocompatibility tumor should provide information about the regulation of autochthonous tumor growth.